Skip to main content

Advertisement

SpringerLink
Log in

Twist is an integrator of SHH, FGF, and BMP signaling

  • Original Article
  • Published:
Anatomy and Embryology Aims and scope Submit manuscript

Abstract

Development of vertebrate embryos is regulated by a number of different signaling pathways. These pathways are frequently not independent of each other but are connected by crosstalk between cells and tissues. Furthermore, different signaling pathways have been found to interact at the cellular level. Development of cranial and limb structures is an example, in which FGF, BMP, and SHH signaling interact. Mutations in the different signaling pathways may therefore result in complex but similar phenotypes. This indicates the existence of integrator molecules, which depend in their expression or activity on the combination of different signaling pathways. Here we show that expression of the bHLH transcription factor Twist in the paraxial mesoderm requires an induction from the notochord. This induction can only be substituted by a combination of FGF and SHH signaling, but not by individual application of FGF8 or SHH alone. Furthermore, the expression of Twist can be modified by BMP2 in a complex, age-dependent manner. We propose that Twist is one of the integrating parts of the three signaling pathways and mediates some of the common effects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1A, B
Fig. 2A, B
Fig. 3A, B
Fig. 4A, B
Fig. 5A–F
Fig. 6
Fig. 7A–C

Similar content being viewed by others

References

  • Bober E, Brand-Saberi B, Ebensperger C, Wilting J, Balling R, Paterson BM, Arnold HH, Christ B (1994) Initial steps of myogenesis in somites are independent of influence from axial structures. Development 120: 3073–3082

    CAS  PubMed  Google Scholar 

  • Bourgeois P, Bolcato-Bellemin AL, et al. (1998) The variable expressivity and incomplete penetrance of the twist-null heterozygous mouse phenotype resemble those of human Saethre-Chotzen syndrome. Hum Mol Genet 7:945–957

    CAS  PubMed  Google Scholar 

  • Brand-Saberi B, Ebensperger C, Wilting J, Balling R, Christ B (1993) The ventralizing effect of the notochord on somite differentiation in chick embryos. Anat Embryol (Berl) 188:239–245

    Google Scholar 

  • Buscher D, Bosse B, Heymer J, Rüther U (1997) Evidence for genetic control of Sonic hedgehog by Gli3 in mouse limb development. Mech Dev 62:175–182

    CAS  PubMed  Google Scholar 

  • Christ B, Brand-Saberi B, Grim M, Wilting J (1992) Local signalling in dermomyotomal cell type specification. Anat Embryol (Berl) 186:505-510

    Google Scholar 

  • Buscher D, Rüther U (1998) Expression profile of Gli family members and Shh in normal and mutant mouse limb development. Dev Dyn 211:88–96

    CAS  PubMed  Google Scholar 

  • Dai P, Akimaru H, Tanaka Y, Maekawa T, Nakafuku M, Ishii S. (1999) Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. J Biol Chem 274:8143–8152

    CAS  PubMed  Google Scholar 

  • Dudley AT, Lyons KM, Robertson EJ (1995) A requirement for bone morphogenetic protein-7 during development of the mammalian kidney and eye. Genes Dev 9:2795–2807

    CAS  PubMed  Google Scholar 

  • Dunn NR, Winnier GE, Hargett LK, et al. (1997) Haploinsufficient phenotypes in Bmp4 heterozygous null mice and modification by mutations in Gli3 and Alx4. Dev Biol 188:235–247

    Article  CAS  PubMed  Google Scholar 

  • Echelard Y, Epstein DJ, St-Jacques B, et al. (1993) Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75:1417–1430

    CAS  PubMed  Google Scholar 

  • El Ghouzzi V, Le Merrer M, Perrin-Schmitt F, et al. (1997) Mutations of the twist gene in Saethre-Chotzen syndrome. Nature Genet. 15:42–46

    Google Scholar 

  • Füchtbauer EM (1995) Expression of M-twist during postimplantation development of the mouse. Dev Dynamics 204:316–322

    Google Scholar 

  • Füchtbauer EM (2002) Inhibition of skeletal muscle development: less differentiation gives more muscle. Results Probl Cell Differ 38:143–161

    PubMed  Google Scholar 

  • Funato N, Ohtani K, Ohyama K, et al. (2001) Common regulation of growth arrest and differentiation of osteoblasts by helix-loop-helix factors. Mol Cell Biol 21:7416–7428

    CAS  PubMed  Google Scholar 

  • Grindley JC, Bellusci S, Perkins D, Hogan BL (1997) Evidence for the involvement of the Gli gene family in embryonic mouse lung development. Dev Biol 188:337–348

    CAS  PubMed  Google Scholar 

  • Hamamori Y, Wu HY, Sartorelli V, Kedes L (1997) The basic domain of myogenic basic helix-loop-helix (bHLH) proteins is the novel target for direct inhibition by another bHLH protein, Twist. Mol Cell Biol 17:6563–6573

    Google Scholar 

  • Hamburger V, Hamilton HL (1992) A series of normal stages in the development of the chick embryo (original from 1951). Dev Dyn 195:231–272

    CAS  PubMed  Google Scholar 

  • Hebrok M, Füchtbauer A, Füchtbauer EM (1997) Repression of muscle-specific gene activation by the murine twist protein. Exp Cell Res 232:295–303

    CAS  PubMed  Google Scholar 

  • Hebrok M, Wertz K, Füchtbauer EM (1994) M-twist is an inhibitor of muscle differentiation. Dev Biol 165:537–544

    Article  CAS  PubMed  Google Scholar 

  • Hofmann C, Luo G, Balling R, Karsenty G (1996) Analysis of limb patterning in BMP-7-deficient mice. Dev Genet 19:43–50

    Article  CAS  PubMed  Google Scholar 

  • Hopwood ND, Pluck A, Gurdon, JB (1989) Xenopus twist is expressed in response to induction in the mesoderm and the neural crest. Cell 59:893–903

    CAS  PubMed  Google Scholar 

  • Incardona JP, Gaffield W, Kapur RP, Roelink H (1998) The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction. Development 125:3553–3562

    CAS  PubMed  Google Scholar 

  • Kalff-Suske M, Wild A, Topp J, et al. (1999) Point mutations throughout the GLI3 gene cause Greig cephalopolysyndactyly syndrome. Hum Mol Genet 8:1769–1777

    CAS  PubMed  Google Scholar 

  • Kanegae Y, Tavares AT, Izpisua B, et al. (1998) Role of Rel/NF-kappaB transcription factors during the outgrowth of the vertebrate limb [see comments]. Nature 392:611–614

    Article  CAS  PubMed  Google Scholar 

  • Kang S, Graham JM, Jr, Olney AH, Biesecker LG (1997) GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nat Genet 15:266–268

    CAS  PubMed  Google Scholar 

  • Krebs I, Weis I, Hudler M, et al. (1997) Translocation breakpoint maps 5 kb 3’ from Twist in a patient with Saethre-Chotzen syndrom. Hum. Mol Gen 8:1079–1086

    Article  Google Scholar 

  • Luo G, Hofmann C, Bronckers AL, et al. (1995) BMP-7 is an inducer of nephrogenesis, and is also required for eye development and skeletal patterning. Genes Dev 9:2808–2820

    CAS  PubMed  Google Scholar 

  • Maestro R, Dei Tos AP, Hamamori Y, et al. (1999) Twist is a potential oncogene that inhibits apoptosis. Genes Dev 13:2207–2217

    Article  CAS  PubMed  Google Scholar 

  • Murray SS, Glackin CA, Winters KA, et al. (1992) Expression of helix-loop-helix regulatory genes during differentiation of mouse osteoblastic cells. J Bone Min Res 7:1131–1138

    CAS  Google Scholar 

  • O’Rourke MP, Soo K, Behringer RR, et al. (2002) Twist plays an essential role in FGF and SHH signal transduction during mouse limb development. Dev Biol 248:143–156

    Article  PubMed  Google Scholar 

  • Nieto MA, Patel K, Wilkinson DG (1996) In situ hybridization analysis of chick embryos in whole mount and tissue sections. Methods Cell Biol 51:219-235

    CAS  PubMed  Google Scholar 

  • Pourquié O, Fan CM, Coltey M, et al. (1996) Lateral and axial signals involved in avian somite patterning: a role for BMP4. Cell 84:461–471

    Google Scholar 

  • Rice DP, Aberg T, Chan Y, et al. (2000) Integration of FGF and Twist in calvarial bone and suture development. Development 127:1845–1855

    CAS  PubMed  Google Scholar 

  • Rohwedel J, Horák V, Hebrok M, et al. (1995) M-twist expression inhibits mouse embryonic stem cell-derived myogenic differentiation in vitro. Exp Cell Res 220:92–100

    Article  CAS  PubMed  Google Scholar 

  • Scaal M, Füchtbauer EM, Brand-Saberi B (2001) cDermo-1 expression indicates a role in avian skin development. Anat Embryol (Berl) 203:1–7

    Google Scholar 

  • Scaal M, Prols F, Füchtbauer EM, et al. (2002) BMPs induce dermal markers and ectopic feather tracts. Mech Dev 110:51–60

    Article  CAS  PubMed  Google Scholar 

  • Schmidt C, Christ B, Patel K, Brand-Saberi B (1998) Experimental induction of BMP-4 expression leads to apoptosis in the paraxial and lateral plate mesoderm. Dev Biol 202:253–263

    Article  CAS  PubMed  Google Scholar 

  • Schneider RA, Hu D, Rubenstein JL, et al. (2001) Local retinoid signaling coordinates forebrain and facial morphogenesis by maintaining FGF8 and SHH. Development 128:2755–2767

    CAS  PubMed  Google Scholar 

  • Shishido E, Higashijima S, Emori Y, Saigo K (1993) Two FGF-receptor homologues of Drosophila: one is expressed in mesodermal primordium in early embryos. Development 117:751–761

    CAS  PubMed  Google Scholar 

  • Simpson P (1983) Maternal-zygotic gene interactions during formation of the dorsoventral pattern in Drosophila embryos. Genetics 105:615–632

    Google Scholar 

  • Soo K, O’Rourke MP, Khoo PL, et al. (2002) Twist function is required for the morphogenesis of the cephalic neural tube and the differentiation of the cranial neural crest cells in the mouse embryo. Dev Biol 247:251–270

    Article  CAS  PubMed  Google Scholar 

  • Sosic D, Richardson JA, Yu K, et al. (2003) Twist regulates cytokine gene expression through a negative feedback loop that represses NF-kappaB activity. Cell 112:169–180

    Article  CAS  PubMed  Google Scholar 

  • Spicer, DB, Rhee J, Cheung WL, Lassar AB (1996) Inhibition of myogenic bHLH and MEF2 transcription factors by the bHLH protein twist. Science 272:1476–1480

    CAS  PubMed  Google Scholar 

  • Stoetzel C, Weber B, Burgeouis P, et al. (1995) Dorso-ventral and rostro-caudal sequential expression of M-twist in the post implantation murine embryo. MOD 51:251–263

    Article  CAS  PubMed  Google Scholar 

  • Stolte D, Huang R, Christ B (2002) Spatial and temporal pattern of Fgf-8 expression during chicken development. Anat Embryol (Berl) 205:1–6

    Google Scholar 

  • Storm EE, Rubenstein JL, Martin GR (2003) Dosage of Fgf8 determines whether cell survival is positively or negatively regulated in the developing forebrain. Proc Natl Acad Sci USA 100:1757–62

    Article  CAS  PubMed  Google Scholar 

  • Suzuki T, Takeuchi J, Koshiba-Takeuchi K, Ogura T (2004) Tbx Genes Specify Posterior Digit Identity through Shh and BMP Signaling. Dev Cell 6:43–53

    Google Scholar 

  • Tamura M, Noda M (1999) Identification of DERMO-1 as a member of helix-loop-helix type transcription factors expressed in osteoblastic cells. J Cell Biochem 72:167–176

    Article  CAS  PubMed  Google Scholar 

  • Tavares AT, Izpisuja-Belmonte JC, Rodriguez-Leon J (2001) Developmental expression of chick twist and its regulation during limb patterning. Int J Dev Biol 45:707–713

    CAS  PubMed  Google Scholar 

  • Thisse B, el Messal M, Perrin-Schmitt F (1987) The twist gene: isolation of a Drosophila zygotic gene necessary for the establishment of dorsoventral pattern. Nucleic Acids Res 15:3439–3453

    CAS  PubMed  Google Scholar 

  • Villavicencio EH, Walterhouse DO, Iannaccone PM (2000) The sonic hedgehog-patched-gli pathway in human development and disease. Am J Hum Genet 67:1047–1054

    CAS  PubMed  Google Scholar 

  • Villavicencio EH, Yoon JW, Frank DJ, et al. (2002) Cooperative E-box regulation of human GLI1 by Twist and USF. Genesis 32:247–58

    Article  CAS  PubMed  Google Scholar 

  • Wolf C, Thisse C, Stoetzel C, et al. (1991) The M-twist gene of Mus is expressed in subsets of mesodermal cells and is closely related to the Xenopus X-twi and the Drosophila twist genes. Dev Biol 143:363–373

    CAS  PubMed  Google Scholar 

  • Zuniga A, Haramis AP, McMahon AP, Zeller R (1999) Signal relay by BMP antagonism controls the SHH/FGF4 feedback loop in vertebrate limb buds. Nature 401:598–602

    Article  CAS  PubMed  Google Scholar 

  • Zuniga A, Quillet R, Perrin-Schmitt F, Zeller R (2002) Mouse Twist is required for fibroblast growth factor-mediated epithelial-mesenchymal signalling and cell survival during limb morphogenesis. Mech Dev 114:51–59

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Ulrike Pein, Ellen Gimbel, and Tina Engist for excellent technical assistance and Morten Kold for help with digital imaging. The project was supported by grants from the Deutsche Forschungsgemeinschaft (FU329/2–2), the Danish Kraeftens Bekaempelse (DP00086) and the Centre of Excellence 592/Project B4 (to B.B.-S.).

Author information

Authors and Affiliations

  1. Institute of Anatomy and Cell Biology, Department II, Albert-Ludwigs-University, Freiburg, Germany

    Christoph Hornik, Beate Brand-Saberi, Stefan Rudloff & Bodo Christ

  2. Department of Molecular Biology, Aarhus University, C.-F. Møllers Allé 130, 8000 , Århus C, Denmark

    Ernst-Martin Füchtbauer

Authors
  1. Christoph Hornik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Beate Brand-Saberi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stefan Rudloff
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bodo Christ
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ernst-Martin Füchtbauer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ernst-Martin Füchtbauer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hornik, C., Brand-Saberi, B., Rudloff, S. et al. Twist is an integrator of SHH, FGF, and BMP signaling. Anat Embryol 209, 31–39 (2004). https://doi.org/10.1007/s00429-004-0412-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00429-004-0412-3

Keywords

Search

Navigation